enantioselective protonation: fundamental insights and new concepts
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Enantioselective Protonation: Fundamental Insights and New Concepts. A presentation by Guillaume Pelletier Literature meeting October 12 th 2011. Enantioselective Protonnation : An Extremely Simple Transformation!(?). - PowerPoint PPT PresentationTRANSCRIPT
Enantioselective Protonation: Fundamental Insights and New
Concepts
• A presentation by Guillaume Pelletier
• Literature meeting October 12th 2011
Enantioselective Protonnation : An Extremely Simple Transformation!(?)
R1
R2
O
R3
R2
O•
R1
R1 O
R3
R2
R1
R3
OM
-H
R3 M
R2 M
H
X*
H
X*
Si
Re
X* M
X* MH2O
H
R2
O
R3R1
O
R3H
R2R1
(R)
(S)
• Enolates are important as synthetic intermediates Enolates are important as synthetic intermediates : regio and stereoselective generation with the desired counterion, increased knowledge of their structure and reactivity
• Enantioselective protonnation via enol tautomerisation Enantioselective protonnation via enol tautomerisation : require only catalytic amounts of chiral reagent.
• Protonnation of a chiral enolate/ligand complexProtonnation of a chiral enolate/ligand complex
What is the Important Facts to Know Before Exploring «AP» of Enolates
• Enantioselective protonation processes are necessarily kinetically controlled kinetically controlled reactions reactions
• Match the ppKKaa of the proton donnor and the product
• Be concerned about the stereochemistry of the proton acceptor stereochemistry of the proton acceptor : the ability to generate a stereodefined proton acceptor is critical (or not) in order to have good enantioselectivity
• Detailed mechanistic explanations are rare : mixture of many mechanismsmixture of many mechanisms
Presentation Outline
• Lucette Duhamel and J.-C. Plaquevent’s Asymmetric Protonation of Benzylidene Glycinates (1978)
• Charles Fehr’s Synthesis of α- and γ-Damascone (1988)
• Hisashi Yamamoto’s Catalytic Asymmetric Protonation of Silyl Enol Ether with LBA (1994)
• Recent Contributions (Levacher, Genet, Fu, Stoltz…) (2005+)
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.Eames, J.; Weerasooriya, N. Tetrahedron : Asymmetry 2001, 12, 1-24.Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron : Asymmetry 2004, 15, 3653-3691.Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nature Chem. 2009, 1, 359-369.
First « Synthetically Useful » Example of AP with Substituted Benzylidene Glycinates
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
R1
N
O
O
R2
(±)
LDA (1.40 equiv)-50 °C, 5 min R1
N
O
O
R2
Li
R1
N
O
O
R2 *
enantioenriched
-70 °C, 15 min
Chiral proton donnor(2.85 equiv)
Influence of the Chiral Acid
CO2H
OH
CO2H
O
O
t-Bu
OH
O
CF3
MeOOH
O
NPhthMe
CO2HHO2C
OCOt-Bu
OCOt-Bu
CO2HMeO2C
OCOt-Bu
OCOt-BuHO2C
CO2H
O
O
HO2C
CO2H
O
O
Ph
85%, 2.4% ee 85%, 5.8% ee 85%, 14.3% ee 80%, 4.0% ee
85%, 50% ee 80%, 19.5% ee 80%, 1.2% ee 80%, 1.6% ee
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Ph
N
O
O
R2
(±)
LDA (1.40 equiv)-50 °C, 5 min Ph
N
O
O
R2
Li
Ph
N
O
O
R2 *
enantioenriched
H-A* (2.85 equiv)-70 °C, 15 min
Influence of the Tartaric Acyl Substituents
Entry R3 Yield (%) ee (%) [α]D25
1 Me 85 2.6 ‒2.2 (S)
2 i-Pr 85 12.1 ‒10.5 (S)
3 t-Bu 85 50 ‒41.9 (S)
4 1-adamantyl 79 53.2 -44.7 (S)
5 Ph 80 12.3 -10.3 (S)
6 CH2Ph 81 8.5 -6.95 (S)
7 (CH2)2Ph 83 6.5 +0.4 (R)Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Ph
N
O
O
R2
(±)
LDA (1.40 equiv)-50 °C, 5 min Ph
N
O
O
R2
Li
OCOR3
CO2HHO2C
OCOR3
Ph
N
O
O
R2 *
enantioenriched
(2.85 equiv)
-70 °C, 15 min
R1
N
O
O
R2
(±)
LDA (1.40 equiv)-50 °C, 5 min R1
N
O
O
R2
Li
R1
N
O
O
R2 *
enantioenriched
-70 °C, 15 min
OCOt-Bu
CO2HHO2C
OCOt-Bu(2.85 equiv)
Influence of the Amino Acid Side-Chain
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Ph
N
O
O
N
O
O
Ph
N
O
O
HN
N
O
O
Ph
N
O
O
85%, 50% ee 85%, 48% ee 65%, 26% ee
95%, 30% ee 82%, 33% ee
N
O
O
Ph
N
O
O
95%, 70% ee
(H+ quench at -105 °C)
MeO
45%, 36% ee (R)(+55% Z-enone)
N
O
O
42%, 34% ee (R)(+58% Z-enone)
(E:Z = 100:0)
(98% ee)
Influence of the Benzylidene Electronic Properties
Entry R2 Yield (%) ee (%)
1 p-CN 75 12.3
2 p-Cl 75 31.3
3 H 85 50
4 p-CH3 82 55
5 o-OMe 70 36.6
6 p-OMe 70 57
7 p-NMe2 75 61Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Ph
N
O
O
R2
(±)
LDA (1.40 equiv)-50 °C, 5 min Ph
N
O
O
R2
Li
OCOt-Bu
CO2HHO2C
OCOt-BuPh
N
O
O
R2 *
enantioenriched
(2.85 equiv)
-70 °C, 15 min
Influence of the Base Additive
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
NLi N
Li
NLi
N
Li
Ph (R) N
Me
R
LiR = Me, 70%, 60.6% eeR = Et, 84%, 70.2% eeR = i-Pr, 75%, 62.3% ee
Ph (R) N
Me
Li OCOt-Bu
CO2HHO2C
OCOt-Bu
Ph (R) N
Me
Li OCOt-Bu
CO2HHO2C
OCOt-Bu
Ph (R) N
Me
Li OCOt-Bu
CO2HHO2C
OCOt-Bu
85%, 50% ee 80%, 35.6% ee 75%, 22.5% ee70%, 28% ee
75%, 5.6% ee(mismatched)
75%, 38.9% ee 85%, 23.8% ee
Ph
N
O
O(±)
Base (1.40 equiv)-50 °C, 5 min Ph
N
O
OLi
OCOt-Bu
CO2HHO2C
OCOt-BuPh
N
O
O
*
enantioenriched
(2.85 equiv)
-70 °C, 15 min
N
R
R
H
N
O
Ph
MeO
Ph
Li NHR2
N
O
Ph
OMe
Ph
LiR2HN
O
O
R
R
O
O
O
R
R
O
O
O
ROCO
CO2H
H
CO2H
OCOR
H OO
R
O
O
R
(S)-enantiomer
"AP""AP"
(R)-enantiomer
vs
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Results Interpretation
OMeO
PhN
Ph
Li N
Enantioselective Protonation of Open-Chain Enolates Without Internal Chelating Atom
• Proton donnor should be only weakly acidic weakly acidic (pKa~15-20)• Proton donnor should contain an electron-rich groupan electron-rich group with chelating ability• The transferred proton should be located in the proximitiy of the stereogenic centerproximitiy of the stereogenic center• Proton donnor should be readily accessible in both enantiomeric form both enantiomeric form and easily easily
recoverablerecoverable
Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Enantioselective Protonation of Open-Chain Enolates Without Internal Chelating Atom
• Proton donnor should be only weakly acidic weakly acidic (pKa~15-20)• Proton donnor should contain an electron-rich groupan electron-rich group with chelating ability• The transferred proton should be located in the proximitiy of the stereogenic centerproximitiy of the stereogenic center• Proton donnor should be readily accessible in both enantiomeric form both enantiomeric form and easily easily
recoverablerecoverable
Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
NNH
O
MePh
HO N
MePh
ephedrine derivative
Enantioselective Protonation of Open-Chain Enolates Without Internal Chelating Atom
• Proton donnor should be only weakly acidic weakly acidic (pKa~15-20)• Proton donnor should contain an electron-rich groupan electron-rich group with chelating ability• The transferred proton should be located in the proximitiy of the stereogenic centerproximitiy of the stereogenic center• Proton donnor should be readily accessible in both enantiomeric form both enantiomeric form and easily easily
recoverablerecoverable
Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
NNH
O
MePh
HO N
MePh
ephedrine derivative
OMe
O
OMe
OLi
O•
OMgCl
MgCl
ligand
(E:Z ~ 9:1)
MgCl
n-BuLi(1.2 equiv)
(1.3 equiv)
(1.2 equiv) Proton sourceO
*
-Damascone(rose fragrance)
-100 °C
-78 °C
-78 °C
EntryProton source
Enolate composition
Enolate generation
Yield (%)
ee (%)
1 MgCl•MeOLi Grignard 60 58
2 MgCl Ketene 76 51
OMgCl ligand
(E:Z ~ 9:1)
Proton sourceO
*
-Damascone(rose fragrance)
α-Damascone Synthesis – Ligand effect
NNH
O
MePh
EntryProton source
Enolate composition
Enolate generation
Yield (%)
ee (%)
1 MgCl•MeOLi Grignard 60 58
2 MgCl Ketene 76 51
3 MgCl Ketene N.D. 16
4 MgCl•MeOLi Ketene 75 70
5 MgCl•t-BuOLi Ketene 70 79
OMgCl ligand
(E:Z ~ 9:1)
Proton sourceO
*
-Damascone(rose fragrance)
α-Damascone Synthesis – Ligand effect
NNH
O
MePh
HO N
MePh
EntryProton source
Enolate composition
Enolate generation
Yield (%)
ee (%)
1 MgCl•MeOLi Grignard 60 58
2 MgCl Ketene 76 51
3 MgCl Ketene N.D. 16
4 MgCl•MeOLi Ketene 75 70
5 MgCl•t-BuOLi Ketene 70 79
6Ketene
73 84
7 t-BuOH 70 62
OMgCl ligand
(E:Z ~ 9:1)
Proton sourceO
*
-Damascone(rose fragrance)
α-Damascone Synthesis – Ligand effect
NNH
O
MePh
HO N
MePh
LiO N
MePh
MgCl
α-Damascone Synthesis – Enolate Stereoselectivity Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
O•
OTMSMgCl
(1.2 equiv)1)
2) TMSCl3) Fractional distillation
(E:Z 98:2)
NHO
MePh
(1.00 equiv)-70 °C
1) MeLi (1.00 equiv)O
80%, 95% ee
O•
OLi1) n-BuLi (1.00 equiv)-100 to -70 °C
(E:Z 97:3)
O
90%, 96% ee
α-Damascone Synthesis – Enolate Stereoselectivity Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
O•
OTMSMgCl
(1.2 equiv)1)
2) TMSCl3) Fractional distillation
(E:Z 98:2)
NHO
MePh
(1.00 equiv)-70 °C
1) MeLi (1.00 equiv)O
80%, 95% ee
O•
OLi1) n-BuLi (1.00 equiv)-100 to -70 °C
(E:Z 97:3)
O
90%, 96% ee
O
89%, >98% ee
NHO
MePh(0.95 equiv)
-70 °C
then TMSCl
OTMS
(E:Z 1:1)
+
α-Damascone Synthesis – Enolate Stereoselectivity Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
O•
OTMSMgCl
(1.2 equiv)1)
2) TMSCl3) Fractional distillation
(E:Z 98:2)
NHO
MePh
(1.00 equiv)-70 °C
1) MeLi (1.00 equiv)O
80%, 95% ee
O•
OLi1) n-BuLi (1.00 equiv)-100 to -70 °C
(E:Z 97:3)
O
90%, 40% ee
O
89%, >98% ee
NHO
MePh(0.95 equiv)
-70 °C
then TMSCl
OTMS
(E:Z 1:1)
+
(E:Z 1:99<)
OLi
NHO
MePh(1.00 equiv)
-70 °C
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
OMgCl
MgCl
(1.05 equiv)Hexanes, 35 to 45 °C
2)
O
OMe
MeOLi1) n-BuLi (1.2 equiv)-78 to 0 °C, THF
HO N
Ph MeO
(s)--Damascone(E selective)
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
OMgCl
MgCl
(1.05 equiv)Hexanes, 35 to 45 °C
2)
O
OMe
MeOLi1) n-BuLi (1.2 equiv)-78 to 0 °C, THF
HO N
Ph MeO
(s)--Damascone(E selective)H-A* (2.0 equiv)THF/Hexanes
-78 to 0 °C, 60 min(Addition of H-A* to enolate)
H-A* (2.5 equiv)THF/Hexanes0 °C, 60 min
(Addition of enolate to H-A*)
25% ee, 100% Conv.
49% ee, 100% Conv.
γ-Damascone Synthesis – Effect of Alkoxide additives
OMgCl
MgCl
(1.05 equiv)Hexanes, 35 to 45 °C
2)
O
OMe
MeOLi1) n-BuLi (1.2 equiv)-78 to 0 °C, THF
HO N
Ph MeO
(S)--Damascone
H-A* (2.5 equiv)THF/Hexanes0 °C, 60 min
49% ee, 100% Conv.inverse addition
(E selective)
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
γ-Damascone Synthesis – Effect of Alkoxide additives
OMgCl
MgCl
(1.05 equiv)Hexanes, 35 to 45 °C
2)
O
OMe
MeOLi1) n-BuLi (1.2 equiv)-78 to 0 °C, THF
HO N
Ph MeO
(S)--Damascone
H-A* (2.5 equiv)THF/Hexanes0 °C, 60 min
49% ee, 100% Conv.inverse addition
(E selective)
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
1) TMSCl (2.0 equiv)-50 to 20 °C, THF
2) MeLi (1.15 equiv)THF/Et2O, 40 °C, 10 min
OLiHO N
Ph Me
O
(S)--Damascone
Conditions
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
OLiHO N
Ph Me
O
(S)--Damascone
Conditions(Protonation at -50 °C)
Entry
Equiv H-A*
Addition mode
SolventLi-A*
(equiv)
ee (%) at
25% Conv
ee (%) at 50% Conv
ee (%) at
100% Conv
1 1.2 normalTHF/Et2O
none 8 39 62
2 1.2 inverseTHF/Et2O
none 26 35 49
3 1.0 inverseTHF/Et2O
1.0 - 65 68
4 1.0 inverseTHF/Et2O
2.0 - 69 70
5 1.0 inverse THF 2.0 - 75 75
LiO N
Ph Me
Li-A* =
• The elucidation of the reaction mechanism is rendered more complex more complex from the non-non-linear relationship linear relationship between reaction product reaction product and H-A* H-A* enantiomeric purity.
γ-Damascone Synthesis – Effect of Alkoxide additives
OMgCl
MgCl
(1.05 equiv)Hexanes, 35 to 45 °C
2)
O
OMe
MeOLi1) n-BuLi (1.2 equiv)-78 to 0 °C, THF
HO N
Ph MeO
(S)--Damascone
H-A* (2.5 equiv)THF/Hexanes0 °C, 60 min
49% ee, 100% Conv.inverse addition
(E selective)
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
1) TMSCl (2.0 equiv)-50 to 20 °C, THF
2) MeLi (1.15 equiv)THF/Et2O, 40 °C, 10 min
OLiHO N
Ph Me
O
(S)--Damascone
Conditions
1) LDA (3.0 equiv) or n-BuLi (1.5 equiv)(E:Z > 99:1)2)
HO N
Ph Me
O
OMe
(2.0 to3.3 equiv)
36 to 50% ee(4:1 to 3:1 Product:SM)
-100 to -10 °C
α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
O
X
HO N
Ph Me
(S)
O
XOLi
(E:Z >99:1)
O
X
BA A
DeprotonationAsymmetric Protonation
THF
(+)-
X
α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem. Int. Ed. 1993, 32, 1042-1044.
O
X
HO N
Ph Me
(S)
O
X
O
X
BA A
DeprotonationAsymmetric Protonation
THF
(+)-
OLi
(E:Z >99:1)
X
Entry X Deprotonnation Protonnation B/Aee (%)
Yield (%)
1 OMen-BuLi (1.5 equiv)
-78 °C, 2.75 h(‒)-H-A* (2.0 equiv) -100 to -10°C,1.75h 22/78 36 (R) -
2 OMeLDA (3.0 equiv)
-78 °C, 3 h(+)-H-A* (3.3 equiv) -100 to -10°C,2.25h 33/67 50 (S) -
3 OMeLDA (3.0 equiv)
-78 °C, 3 haq. HCl (excess),
-78 °C 72/28 - -
4 SPhn-BuLi (2.0 equiv)
-78 °C, 3 h(‒)-H-A* (2.7 equiv) -100 to -10°C,1.75h 43/57 96 (R) 81
5 SPhLDA (3.0 equiv)-78 °C, 2.75 h
(‒)-H-A* (4.0 equiv) -100 to -10°C,1.5h 56/44 97 (R) 84
6 SPhLDA (1.5 equiv)
-78 °C, 3.5 h(+)-H-A* (2.0 equiv) -100 to -10°C,1.5h 45/55 94 (S) 76
α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
SPhO
SPh
HO N
Ph Me O
SPhOLi
(E:Z > 99:1)
O
SPh
B A
LDA (2.0 equiv)
-78 °C, THF, 2.75 h
(+)-
THF, -100 °C, 1.0 hthen -10 °C, 30 min
(4.0 equiv)
97% ee84% yield (B+A)
A
α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
SPhO
SPh
HO N
Ph Me O
SPhOLi
(E:Z > 99:1)
O
SPh
B A
LDA (2.0 equiv)
-78 °C, THF, 2.75 h
(+)-
THF, -100 °C, 1.0 hthen -10 °C, 30 min
(4.0 equiv)
97% ee84% yield (B+A)
A
OLiO
X
HO N
Ph Me O
XX
(Z:E ~ 19:1) D
n-BuLi (1.5 equiv)
-100 °C, THF2.0 to 4.0 h
( )-
THF, -100 °C, 1.0 hthen -10 °C, 10 min
(2.0 equiv) X = OMe (36% ee)X = OPh (77% ee)
X = SPh (99% ee, 87% yield)X = 2-Naphthyl (99% ee, 82% yield)
C
α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
SPhO
SPh
HO N
Ph Me O
SPhOLi
(E:Z > 99:1)
O
SPh
B A
LDA (2.0 equiv)
-78 °C, THF, 2.75 h
(+)-
THF, -100 °C, 1.0 hthen -10 °C, 30 min
(4.0 equiv)
97% ee84% yield (B+A)
A
OLiO
X
HO N
Ph Me O
XX
(Z:E ~ 19:1) D
n-BuLi (1.5 equiv)
-100 °C, THF2.0 to 4.0 h
( )-
THF, -100 °C, 1.0 hthen -10 °C, 10 min
(2.0 equiv) X = OMe (36% ee)X = OPh (77% ee)
X = SPh (99% ee, 87% yield)X = 2-Naphthyl (99% ee, 82% yield)
C
O•
E
THF, >80 °C
-PhSLi
α-Damascone Synthesis – Catalytic Enantioselective Process
O•
E
>-80 °CSlow
Reversible
+ PhSLi
OLi
SPh
• Slow Slow and reversiblereversible generation of the transient enolate
α-Damascone Synthesis – Catalytic Enantioselective Process
O•
E
>-80 °CSlow
Reversible
+ PhSLi
OLi
SPh
HO N
Ph Me
FastIrreversible
O
SPh
enantioenrichedD
LiO N
Ph Me
• Slow Slow and reversiblereversible generation of the transient enolate• RapidRapid and irreversibleirreversible protonation of the enolate by H-A*
α-Damascone Synthesis – Catalytic Enantioselective Process
O•
E
>-80 °CSlow
Reversible
+ PhSLi
OLi
SPh
HO N
Ph Me
FastIrreversible
O
SPh
enantioenrichedD
LiO N
Ph MePhSH
FastIrreversible
• Slow Slow and reversiblereversible generation of the transient enolate• Rapid Rapid and irreversibleirreversible protonation of the enolate by H-A*• The rate of regenerationrate of regeneration of the catalyst and enolate can be ajusted with the ajusted with the
external proton source external proton source (PhSH)• Proton exchange between A*- and PhSH must be rapidrapid and completecomplete and
PhSLi must be more nucleophilicmore nucleophilic than Li-A*• Background reaction is suppressed by low [PhSH]low [PhSH]
α-Damascone Synthesis – Catalytic Enantioselective Process
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1044-1046.
O•
(1.00 equiv)
O
SArArSH (1.00 equiv), THF
Temperature, Time
LiO
Ph
N
Me(xx equiv)
Entry ArSHLi-A*
(mol %)Temperature
(°C)
ArSH Addition time (h)
ee (%)Yield (%)
1 PhSH 100 -55 3 95 84
2 4-ClPhSh 100 -55 4 97 85
3 PhSH 5 -27 3 89 86
4 PhSH 2 -27 1 77 87
5 4-ClPhSH 5 -27 3 90 81
6 4-ClPhSH 2 -27 3 57 -
Catalytic Enantioselective Protonation – General Scheme
R1
R2
Y
O
R1
R2
Y
O
*
H-A* A*
Z-HZ
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
• With preformed enolates, [enolate] > [H-A*][enolate] > [H-A*]• Formally, an external, achiral proton source Z-H selectively protonates A* Z-H selectively protonates A* - -
and not the enolatenot the enolate• Protonation of A*- should be rapid rapid with Z-H (unless there is a catalytic
enantioselective tautomerisation mechanism)
What About Preformed Enolates? (Autocalatylic)
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
OTMS
MeLi (1.00 equiv)
OLi
HO
MePh
N LiO
MePh
N
O
OLi
H
H
TMSCl
OTMS
O
H
What About Preformed Enolates? (Autocalatylic)
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
• This autocatalytic process is based on subtile kinetic differences in the proton transfer reactions between H-A*, A*-, the enolate and the non-inducing proton donnor (Z-H).
OTMS
MeLi (1.00 equiv)
OLi
HO
MePh
N LiO
MePh
N
O
OLi
H
H
TMSCl
OTMS
O
H
With E:Z = 98:2and 1.0 equiv H-A* : 80%, 95% ee
With E:Z = 98:2and 0.3 equiv H-A* : 86%, 93% ee
Catalytic Enantioselective Protonation – General Scheme
O•
(1.00 equiv)
OLi
n-BuLi (1.05 equiv)
THF, -100 to -70 °C
O
O
OLi
HO
Ph
N
Me
LiO
Ph
N
Me
(E:Z >97:3)
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Catalytic Enantioselective Protonation – General Scheme
O•
(1.00 equiv)
OLi
n-BuLi (1.05 equiv)
THF, -100 to -70 °C
O
O
OLi
HO
Ph
N
Me
LiO
Ph
N
Me
(E:Z >97:3)55% ee with
0.5 equiv of H-A*
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Catalytic Enantioselective Protonation – General Scheme
O•
(1.00 equiv)
n-BuLi (1.05 equiv)
HO
Ph
N
Me
LiO
Ph
N
Me
Ph
O
Ph
OLi
OLi
THF, -100 to -70 °C
O
(E:Z >97:3)
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Catalytic Enantioselective Protonation – General Scheme
O•
(1.00 equiv)
n-BuLi (1.05 equiv)
HO
Ph
N
Me
LiO
Ph
N
Me
Ph
O
Ph
OLi
OLi
THF, -100 to -70 °C
O
(E:Z >97:3)
EntryH-A*
(equiv)PhCH2Ac (equiv)
ee (%)Yield (%)
1 1.1 - 96 90
2 0.2 0.85 94 94
3 0.1 0.95 85 99
4 0.20.8(TMSC
l)98 91
Catalytic Enantioselective Protonation – Protonnation of H-A*/enolate aggregate
n-Bu
OHLi
O
NPh
n-Bu
OHLi
O
Ph
(S)
n-Bu
O
n-Bu
O
(S)-Ketone (RS)-Ketone
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Catalytic Enantioselective Protonation of Cylic Lithium Enolates
Yanagisawa, A.; Kuribayashi, T.; Kikuchi, T.; Yamamoto, H. Angew. Chem., Int. Ed. 1994, 33, 107-109.Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.
n-BuLi (1.1 equiv)
THF, 0 °C, 2 h
OTMS
(1.0 equiv)
OLi O
HN ON
Ph Ph
Z-HZ
O
O
LiN ON
Ph Ph
O
O
Catalytic Enantioselective Protonation of Cylic Lithium Enolates
Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140-5149.Rebek, J., Jr.; Askew, B.; Killoran, M.; Nemeth, D.; Lin, F.-T. J. Am. Chem. Soc. 1987, 109, 2426-2433.
CO2HCO2H
CO2H
(Kemp's triacid)
1) aq. NH4OHDMAP (20 mol%)
110 °C, 12 h
2) SOCl2 (5.0 equiv)reflux, 3 h
HN ClOO
O
79% over 2 steps
H2N OH
Ph Ph
Et3N, DCM2) SOCl2
HN ON
Ph Ph
O
O
1)
92% over 2 steps
n-BuLi (1.1 equiv)
THF, 0 °C, 2 h
OTMS
(1.0 equiv)
OLi O
HN ON
Ph Ph
Z-HZ
O
O
HN ON
Ph Ph
O
O
Catalytic Enantioselective Protonation of Cylic Lithium Enolates
OLi
HN ON
Ph Ph
O
O
(xx equiv)i)
THF, -78 °C, 20 minii) Achiral proton source
(1.0 equiv)Addition over 2 h, -78 °C
O
72-85% yield
EntryAchiral proton
H-A* (equiv)
ee (%)
1 1.0 87
2 0.10 83
3 0.05 72
4 0.10 90
5 0.01 81
6 0.10 88
7 0.01 80
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.
NH
O
O
OH
t-Bu
t-BuMe
t-Bu
O
t-Bu
O
*With a TMSCl quench at -78 °C!*With a TMSCl quench at -78 °C!
Catalytic Enantioselective Protonation of Cylic Lithium Enolates
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.
ON
PhH Ph H
ONO
LiH
R
R O Me
re
si
ON
HPhHPh
O NO
LiH
R
ROMere
si
R
R
OLi
Me
(R)
O
R
R
Me (S)
O
R
R
Me
(R)-Ketone (S)-Ketone
Enantioselective Protonation of Prochiral Silyl Enol Ethers and Ketene Silyl Acetals
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
OTMS
Ph Chiral Brnsted Acid
OTMS
TMSOPh
Me
or
O
Ph
O
TMSOPh
Me
or* *
O
Ph
HL SiMe3
O-Protonnation
C-Protonnation
Enantioselective Protonation of Prochiral Silyl Enol Ethers and Ketene Silyl Acetals
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
OTMS
Ph Chiral Brnsted Acid
OTMS
TMSOPh
Me
or
O
Ph
O
TMSOPh
Me
or* *
O
Ph
HL SiMe3
O-Protonnation
C-Protonnation
• Silyl enol ether is a « stable metal enolate equivalentstable metal enolate equivalent » which can be isolated
• In general, it is difficult the control the enantioselectivity difficult the control the enantioselectivity with protonation of silyl enol ether with chiral Brønsted acids
• Two main reason for poor induction is bonding flexibility bonding flexibility between H and A* and chiral pool chiral pool of H-A* is limited of H-A* is limited to sulfonic and carboxylic acids
Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
OTMS
Ar
OTMS
TMSOAr
R
or
O
Ar
O
MeOAr
R
or
O
O
H
H
Lewis acid assisted chiral Brnsted Acid (LBA)
SnCl4
(1.0 equiv)
-78 °C, Toluene, 1 h
>95% yield
Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
OTMS
Ar
OTMS
TMSOAr
R
or
O
Ar
O
MeOAr
R
or
O
O
H
H
Lewis acid assisted chiral Brnsted Acid (LBA)
SnCl4
(1.0 equiv)
-78 °C, Toluene, 1 h
>95% yield
O
91% ee
O
93% ee
O
42% ee
CO2Me CO2Me
CO2Me
Cl
CO2Me
Cl
Br
92% ee
91% ee 84% ee
60% ee
Enantioselective Protonation of Prochiral Silyl Enol Ethers and Ketene Silyl Acetals
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
O
Sn
Cl
Cl
Cl
O
ClH
R2
R1
OSiR3
O
Sn
Cl
Cl
Cl
O
ClSiR3
PhR2
R1 H
O
+
Asymmetricprotonation
Catalytic Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
O
O
H
H
SnCl4
OTMS
Ph
O
Ph
O
O
TMS
H
SnCl4
OHOTMS
Chiral LBA
Catalytic Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
O
O
H
H
SnCl4
OTMS
Ph
O
Ph
O
OH
SnCl3
OHOTMS
Chiral LBA
TMSCl+
SnCl4
Achiral LBA
Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals
O
O
H
H
SnCl4OTMS
Ph
O
Ph
O
O
Me
H
SnCl4
(R)-BINOL LBA (R)-BINOL-OMe LBA
OH
Me Me
(1.1 equiv)
(slow addition)
SnCl4 (xx mol%)Chiral LBA (xx mol%)
toluene, -80 °C100% conversion
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals
O
O
H
H
SnCl4OTMS
Ph
O
Ph
O
O
Me
H
SnCl4
(R)-BINOL LBA (R)-BINOL-OMe LBA
OH
Me Me
(1.1 equiv)
(slow addition)
SnCl4 (xx mol%)Chiral LBA (xx mol%)
toluene, -80 °C100% conversion
Entry Chiral LBA (mol %)SnCl4
(mol %)Time (h)
ee (%)
1 (R)-BINOL-OMe (2)(2) 110 1 90
2 (R)-BINOL-OMe (5)(5) 110 0.5 91
3 (R)-BINOL (5)(5) 110 0.5 80
4 (R)-BINOL-OMe (2)(2) 50 2 90
5 (R)-BINOL-OMe (20)(20) 16 1 0
6 (R)-BINOL-OMe (100)(100) 100 0.2 98Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals
O
O
H
H
SnCl4OTMS
Ph
O
Ph
O
O
Me
H
SnCl4
(R)-BINOL LBA (R)-BINOL-OMe LBA
OH
Me Me
(1.1 equiv)
(slow addition)
SnCl4 (xx mol%)Chiral LBA (xx mol%)
toluene, -80 °C100% conversion
Entry Chiral LBA (mol %)SnCl4
(mol %)Time (h)
ee (%)
1 (R)-BINOL-OMe (2)(2) 110 1 90
2 (R)-BINOL-OMe (5)(5) 110 0.5 91
3 (R)-BINOL (5)(5) 110 0.5 80
44 ((RR)-BINOL-OMe (2))-BINOL-OMe (2) 5050 22 9090
5 (R)-BINOL-OMe (20)(20) 16 1 0
6 (R)-BINOL-OMe (100)(100) 100 0.2 98Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals
O
O
H
H
SnCl4
OTMS
Ph
O
O
Me
H
SnCl4
(R)-BINOL LBA
(R)-BINOL-OMe LBA
(1.1 equiv)
toluene-d8, -80 °C5 min
O
O
H
SnCl3
OTMS
Ph
(1.1 equiv)
toluene-d8, -80 °C5 min
TMSCl+
O
O
Me
SnCl3
O
OTMS
H
SnCl4+
15% 85%
>95%
0.26 ppm
+0.16 ppm
TMSCl+
+0.16 ppm
• 97% Conversion with (R)-BINOL-OMe LBA vs 17% Conversion with phenol-LBA and 0% with SnCl4 (no acid present)!Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Recent Improvements with Chiral Brønsted Acids (Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247.
n
OTMS
R O
O
i-Pr
i-Pr
t-Bu
PO
NHTfi-Pr
i-Pr t-Bu
n
O
R
Chiral Phosphoramide (5 mol %)
OH
(1.1 equiv)
toluene, rt, 6 to 40 h
Chiral Phosphoramide
Recent Improvements with Chiral Brønsted Acids (Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247.
n
OTMS
R O
O
i-Pr
i-Pr
t-Bu
PO
NHTfi-Pr
i-Pr t-Bu
n
O
R
Chiral Phosphoramide (5 mol %)
OH
(1.1 equiv)
toluene, rt, 6 to 40 h
Chiral Phosphoramide
O O O O
O OO
OMe Cl
O
97%, 82% ee 98%, 84% ee 95%, 84% ee 99%, 87% ee
99%, 90% ee (with 5.0 mol%)99%, 88% ee (with 0.1 mol%)80%, 86% ee (with 0.01 mol%)
97%, 90% ee 97%, 58% ee 96%, 68% ee
Recent Improvements with Chiral Brønsted Acids (Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247.
n
OTMS
R O
O
i-Pr
i-Pr
t-Bu
PO
NHTfi-Pr
i-Pr t-Bu
n
O
R
Chiral Phosphoramide (5 mol %)
OH
(1.1 equiv)
toluene, rt, 6 to 40 h
Chiral Phosphoramide
O
O
Ar
Ar
PO
NHTf+
OH OH2
O
O
Ar
Ar
PO
TfN
Oxonium ion pair
O
PhOxonium ion pair
or H-A*
TMSO
Ph
TMS
HTfNPO(OR*)2
O
PhH
HO TMSO
+ H-A*
Intermediary chiralion pair
Recent Improvements with Chiral Chincona as Latent HF Source
Poisson , T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090-7093.
Ph
O
F+ EtOH
Ph
O
OEt
Generation ofHF
R*N
R*
R*
R*N
R*
R*H
F
Proton Shuttle
OTMS
R
O
RH
In situ Desilylation/Asymmetric Protonation
Recent Improvements with Chiral Chincona as Latent HF Source
Poisson , T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090-7093.
Ph
O
F+ EtOH
Ph
O
OEt
Generation ofHF
R*N
R*
R*
R*N
R*
R*H
F
Proton Shuttle
OTMS
R
O
RH
In situ Desilylation/Asymmetric Protonation
O
R
SiMe3
HN
R*
FO O
OO
N
OMe
N
N
MeO
N
R*3N cat: (DHQ)2AQN
R
OTMSR*
3N cat (10 mol%)
PhCOF (1.05 equiv)
EtOH (1.05 equiv)
DMF, rt, 12 h
R
O
84%, 85% ee (R = Bn) 88%, 81% ee (R = Me)70%, 78% ee (R = Et)
Chiral Guanidine Catalyzed Conjugate Addition/Enantioselective Protonation
Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641-5647.
B*
B*-H Nu
Nu
R1
R2
O B*-H
R1
O
R2
Transient enolate
Nu-H
R1
O
R2
Nu
*
Protonation step
Michael addition
Chiral Guanidine Catalyzed Conjugate Addition/Enantioselective Protonation
Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641-5647.
B*
B*-H Nu
Nu
R1
R2
O B*-H
R1
O
R2
Transient enolate
Nu-H
R1
O
R2
Nu
*
Protonation step
Michael addition
CO2t-Bu(phth)N
NH
N
Nt-Bu t-Bu
(10 mol%)
ArSH (1.10 equiv)-50 °C, Et2O, 0.5 to 4 h
CO2t-Bu(phth)N
SAr
NH
N
Nt-Bu t-Bu
(10 mol%)
(R)2POH (1.10 equiv)0 °C, toluene, 1.5 to 8 h
N
O
O
MesN
O
O
Mes
PO
RR
ArSH = PhSH (90% ee) = 2-CF3SH (93% ee) = Thiophen-2-ylSH (91% ee)
92-99% yield
H
H
79-95% yield
(R)2POH = (2-EtC6H4)2POH (92% ee) = (3-ClC6H4)2POH (92% ee) = (naphth-1-yl)2POH (98% ee)
Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
NHAc
CO2Me
+ ArBF3K
[Rh(cod)2]+PF6- (3 mol%)
(R,R)-BINAP (6.6 mol%)
Guaiacol (1.0 equiv)
toluene, 110 °C, 20 h
NHAc
CO2Me
Ar
OMe
OH
Guaiacol
NHAc
CO2Me
NHAc
CO2Me
NHAc
CO2Me
NHAc
CO2Me
NHAc
CO2Me
NHAc
CO2Me
MeO
F
S
Me
89%, 90% ee 89%, 90% ee 88%, 87% ee
66%, 89% ee68%, 81% ee82%, 83% ee
Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
RhL
PP
OR
* Ar BF3K
RO BF3K
RhL
PP
Ar
*
RhPP
Ar
* NHAc
CO2Me
LNHAcMeO2C
RhPP
*
O
MeO2CNHAc
Ar
RO HL +
O
MeO2CNHAc
Ar
*
RO H
Ar H
Transmetallation
Coordination to Amidoacrylate
Carbo-rhodation(Insertion of Ar)
Oxa- -allylrhodiumIntermediate
Protonation f rom the Re Face
Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
NHPG
CO2R
+ PhBF3K
[Rh(cod)2]+PF6- (3 mol%)
(R,R)-BINAP (6.6 mol%)
guaiacol (1.0 equiv)toluene, 110 °C, 20 h
NHPG
CO2R
Ph
Entry PG RpKa
of SMYield (%)
ee (%)pKa of Prod
1 Ac Me 13.1 91 90 14.7
2 CBz Me 9.4 92 43 11.0
3 Boc Me 9.6 82 90 11.2
4 Phth Me - 91 10 -
5COCF
3Me 8.05 100 15 9.67
6 Ac i-Pr - 87 91 -
7 Boc i-Pr - 76 93 -
8 Boc t-Bu - 70 95 -
Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
NAc
CO2Me
+ PhBF3K
[Rh(cod)2]+PF6- (3 mol%)
(R,R)-BINAP (6.6 mol%)
Guaiacol (1.0 equiv)
toluene, 110 °C, 20 h
NAc
CO2Me
Ph
OMe
OH
Guaiacol
Me
12%, 20% ee
Me
NHAc
CO2Me
+ PhBF3K
[Rh(cod)2]+PF6- (3 mol%)
(R,R)-BINAP (6.6 mol%)
(R)- or (S)- or
rac-BINOL (1.0 equiv)
toluene, 110 °C, 20 h
NHAc
CO2Me
Ph
27% ee
NHAc
CO2Me
+ PhBF3K
[Rh(cod)2]+PF6- (3 mol%)
(R,R)-BINAP (6.6 mol%)
Guaiacol-d (1.0 equiv)
toluene, 110 °C, 20 h
NHAc
CO2Me
Ph
81%, 90% ee28% D incorporation
D
NHAc
CO2Me
+ PhBF3K
[Rh(cod)2]+PF6- (3 mol%)
(R)-Difluorphos (6.6 mol%)
Guaiacol (1.0 equiv)
toluene, 110 °C, 20 h
NHAc
CO2Me
Ph
86%, 92% ee
O
O
O
O
F
F
F
F
PPh2
PPh2
(R)-Difluorphos
Protonation by Chiral Brønsted Base – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
Catalyst
RLO
•
RS
cat.
O
RS
RL
RO H
cat.
O
RS
RL
H*
OR
RO
O
RS
RL
H*
Protonation by Chiral Brønsted Base – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
• ee% of product varies linearly with with ee% of starting catalyst
NOR
Me
Me
Me Me
Me
FeR = OMe, 27% eeR = OTES, 28% eeR = OTBS, 77% ee (87%)R = OTBDPS, 68% ee
R
R
R R
R
FeN
Me2N
R = Ph, >5% eeR = Me, >5% ee
MeO
•
Ph
+ MeOHcat. (10 mol%)
2,6-di-t-butylpyridinium triflate (12 mol%)toluene, -78 °C, 24 h
O
MeO
Me
Ph
cat. =
NOR
Me
Me
Me Me
Me
FeNH
OR
Me
Me
Me Me
Me
Fe
MeOH + OMe
MeO
•
Ph
+ MeOHcat. (10 mol%)
toluene, -78 °C, 24 h
O
MeO
Me
Ph
56% ee
Fe
N
Me
Me
Me
Me
Me
OTBS
O
Ph
Me
H
Fe
N
Me
Me
Me
Me
Me
OTBS
O
Ph Me
H
MeO MeO
O
MeOMe
H Ph
O
MeOPh
H Me
S- Unfavored
Fe
N
Me
Me
Me
Me
Me
OTBS
O
Me
Ph
H
Fe
N
Me
Me
Me
Me
Me
OTBS
O
Me Ph
H
R- Favored
Protonation by Chiral Brønsted Base – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.M. Poirier Literature Meeting (Oct 2th 2007)
Protonation by Chiral Brønsted Acid – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
Me
Me
Me Me
Me
FeN
Me2N
EtO
•
Ph
+
Chiral DMAP (3 mol%)
toluene, rt, 2 h
O
O
Et
Ph
PhOH +
Me
Me
Me Me
Me
FeN
Me2N
HPhO
OH
R
t-Bu
R = (H), 47% eeR = (4-CF3), 35% eeR = (4-MeO), 72% eeR = (2-MeO), 80% ee
R = 2-(Me), 81% eeR = 2-(i-Pr), 80% eeR = 2-(Ph), 81% eeR = 2-(t-Bu), 91% ee (89%)
R OH R
(1.04 equiv)
O
OPh
t-Bu
O
O
Me
PMP
t-Bu
O
O
t-Bu
S
87%, 88% ee 78%, 94% ee 94%, 79% ee
Protonation by Chiral Brønsted Acid – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
Catalyst
RLO
•
RS
RO H
RO
O
RS
RL
RO
O
RS
RL
H*
cat. H OR
cat. H
Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045.
OMe
O
O
PPh2 N
O
t-BuPd2(dba)3
Et2O, rt, 10 h
O
Me
PdN P
*
OMe
97%, 92% ee
Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045.
OMe
O
O
PPh2 N
O
t-BuPd2(dba)3
Et2O, rt, 10 h
O
Me
PdN P
*
OMe
97%, 92% ee
H
OMe
H
?
Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
OMe
O
O
PPh2 N
O
t-Bu
Pd(OAc)2 (10 mol%)
HCO2H (2.5 equiv), 4Å MSDioxane [0.033M], 3 to 22 h
(12.5 mol%)
OMe
H
88%, 94% ee
Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
OMe
O
O
PPh2 N
O
t-Bu
Pd(OAc)2 (10 mol%)
HCO2H (2.5 equiv), 4Å MSDioxane [0.033M], 3 to 22 h
(12.5 mol%)
OMe
H
88%, 94% ee
OF
H
79%, 88% ee
MeO
MeO
OMe
H
62%, 94% ee
Bn
O
91%, 92% ee
H
NBn
O
81%, 84% ee
H
Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
OMe
O
O
PPh2 N
O
t-Bu
Pd(OAc)2 (10 mol%)
HCO2H (2.5 equiv), 4Å MSDioxane [0.033M], 3 to 22 h
(12.5 mol%)
OMe
H
88%, 94% ee
OF
H
79%, 88% ee
MeO
MeO
OMe
H
62%, 94% ee
Bn
O
91%, 92% ee
H
NBn
O
81%, 84% ee
H
• Excess of HCO2H led to decreased enantioselectivitydecreased enantioselectivity, while smaller amounts of HCO2H increased allylation.increased allylation.
• Small amount of 4Å MS decreased enantioselectivity, decreased enantioselectivity, while large quantity increased allylation.increased allylation.
• 5-8 equiv of HCO5-8 equiv of HCO22H H and 1.80g 4Å MS/mmol 1.80g 4Å MS/mmol substrate was optimal…
Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
OMe
O
O
PPh2 N
O
t-Bu
Pd2(dba)2 (5 mol%)
Meldrum's acid (2.5 equiv)Dioxane [0.033M], 0.5 to 5 h
(12.5 mol%)
OMe
H
86%, 90% ee (on 0.1 mmol)86%, 77% ee (on 0.3 mmol)
O O
O O
Meldrum's acid
HO
86%, 90% ee (on 0.1 mmol)86%, 77% ee (on 0.3 mmol)
HO
99%, 92% ee (on 0.1 mmol)99%, 89% ee (on 0.3 mmol)
H
OTBDPS
O
97%, 85% ee (on 0.1 mmol)97%, 80% ee (on 0.3 mmol) 79%, 61% ee (on 0.3 mmol)
O
Me
H
Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
PdL
P N
L
*
- CO2
O
OO
O
OO
Pd
L
P
N
*O
Pd
OOP N
*
PdO
P N
*
O O
O O
HO
R
O O
O O
PdP N
*
O O
OO
Concluding Remarks – Take Home Message
S
CO2H
Me
CO2H
AMDase (cat.)Tris/HCl buffer
H2O
Me
Ar
O
O
O
OH
HS
Cys188
Gly78
-CO2 S
CO2H
Me
H
Wild-type enzyme, 99% eeG74C mutant, 0% ee
G74C/C1885 mutant, -94% ee
Matoishi, K.; Ueda, M.; Miyamoto, M.; Ohta, H. J. Mol. Catal. B 2004, 27, 161-168.Blanchet, J.; Baudoux, J.; Amere, M.; Lasne, M.-C.; Rouden, J. Eur. J. Org. Chem. 2008, 5493-5506.
• A great deal of energy has been put to introduce a simple proton to form chiral enantioenriched tertiary carbon center
• Although we have ennumerated numerous parameters that are critical to achieve high enantioselectivities, few mechanistic understanding of their behaviour are proposed yet.
• ‘‘AP’’ can be used for making α- and β-amino acids and few natural products• Enantioselective protonnation should continue to rise as an important tool for understanding
general organic chemistry